1. Field of the Invention
The present invention is related to the use of compounds and pharmaceutical compositions that inhibit the Toll-Like Receptor signaling pathway to prevent or treat diseases or disorders. The invention further relates to the treatment of hypercholesterolemia and hyperlipidemia and diseases related thereto.
2. Summary of the Related Art
Due to their insolubility in blood, cholesterol and lipids are transported in the circulatory system in lipoproteins. Cholesterol and lipid in lipoproteins can be deposited in tissues throughout the circulatory system. High concentrations of cholesterol (hypercholesterolemia) and/or lipid (hyperlipidemia) in the circulatory system are conditions known to be associated with many diseases, including, but not limited to, coronary heart disease, arteriosclerosis, atherosclerosis, stroke, peripheral vascular disease, diabetes and high blood pressure. It has been established that lowering low density lipoprotein lipid and/or low density lipoprotein cholesterol concentration in the blood is beneficial for protecting against diseases associated with high blood concentrations of cholesterol and/or lipids. It has been further established that increasing the concentration of high density lipoprotein lipid and/or high density lipoprotein cholesterol concentration in relation to the concentration of low density lipoprotein lipid and/or low density lipoprotein cholesterol concentration in the blood is beneficial for protecting against diseases associated with high blood concentrations of cholesterol and/or lipids.
Toll-like receptors (TLRs) are present on many cells of the immune system and have been shown to be involved in the innate immune response (Hornung, V. et al. (2002) J. Immunol. 168:4531-4537). TLRs are a key means by which mammals recognize and mount an immune response to foreign molecules and also provide a means by which the innate and adaptive immune responses are linked (Akira, S. et al. (2001) Nature Immunol. 2:675-680; Medzhitov, R. (2001) Nature Rev. Immunol. 1:135-145). In mammals, this family consists of at least eleven proteins called TLR1 to TLR11, which are known to recognize pathogen associated molecular patterns (PAMPs) from bacteria, fungi, parasites and viruses and induce an immune response mediated by a number of transcription factors (Poltorak, A. et al. (1998) Science 282:2085-2088; Underhill, D. M., et al. (1999) Nature 401:811-815; Hayashi, F. et al. (2001) Nature 410:1099-1103; Zhang, D. et al. (2004) Science 303:1522-1526; Meier, A. et al. (2003) Cell. Microbiol. 5:561-570; Campos, M. A. et al. (2001) J. Immunol. 167: 416-423; Hoebe, K. et al. (2003) Nature 424: 743-748; Lund, J. (2003) J. Exp. Med. 198:513-520; Heil, F. et al. (2004) Science 303:1526-1529; Diebold, S. S., et al. (2004) Science 303:1529-1531; Hornung, V. et al. (2004) J. Immunol. 173:5935-5943). TLRs are known to be a key means by which mammals recognize and mount an immune response to foreign molecules and are also recognized as providing a means by which the innate and adaptive immune responses are linked (Akira, S. et al. (2001) Nature Immunol. 2:675-680; Medzhitov, R. (2001) Nature Rev. Immunol. 1:135-145).
Some TLRs are located on the cell surface to detect and initiate a response to extracellular pathogens and other TLRs are located inside the cell to detect and initiate a response to intracellular pathogens. Table 1 provides a representation of TLRs, the known agonists therefore and the cell types known to contain the TLR (Diebold, S. S. et al. (2004) Science 303:1529-1531; Liew, F. et al. (2005) Nature 5:446-458; Hemmi H et al. (2002) Nat. Immunol. 3:196-200; Jurk M et al. (2002) Nat. Immunol. 3:499; Lee J et al. (2003) Proc. Natl. Acad. Sci. USA 100:6646-6651); (Alexopoulou, L. (2001) Nature 413:732-738).
TABLE 1Cell Types ContainingTLR MoleculeAgonistReceptorCell SurfaceTLRs:TLR2bacterial lipopeptidesMonocytes/macrophages,Myeloid dendritic cells,Mast cellsTLR4gram negative bacteriaMonocytes/macrophages,Myeloid dendritic cells,Mast cells,Intestinal epitheliumTLR5motile bacteriaMonocyte/macrophages,Dendritic cells,Intestinal epitheliumTLR6gram positive bacteriaMonocytes/macrophages,Mast cells,B lymphocytesEndosomalTLRs:TLR3double stranded RNADendritic cells,virusesB lymphocytesTLR7single stranded RNAMonocytes/macrophages,viruses; RNA-Plasmacytoidimmunoglobulin complexesdendritic cells,B lymphocytesTLR8single stranded RNAMonocytes/macrophages,viruses; RNA-Dendritic cells,immunoglobulin complexesMast cellsTLR9DNA containingMonocytes/macrophages,unmethylated “CpG”Plasmacytoidmotifs; DNA-dendritic cells,immunoglobulin complexesB lymphocytes
The selective localization of TLRs and the signaling generated therefrom, provides some insight into their role in the immune response. The immune response involves both an innate and an adaptive response based upon the subset of cells involved in the response. For example, the T helper (Th) cells involved in classical cell-mediated functions such as delayed-type hypersensitivity and activation of cytotoxic T lymphocytes (CTLs) are Th1 cells. This response is the body's innate response to antigen (e.g., viral infections, intracellular pathogens, and tumor cells), and results in a secretion of IFN-gamma and a concomitant activation of CTLs.
As a result of their involvement in regulating an inflammatory response, activation of TLRs has been shown to play a role in the pathogenesis of many diseases, including autoimmunity, infectious disease and inflammation (Papadimitraki et al. (2007) J. Autoimmun. 29: 310-318; Sun et al. (2007) Inflam. Allergy Drug Targets 6:223-235; Diebold (2008) Adv. Drug Deliv. Rev. 60:813-823; Cook, D. N. et al. (2004) Nature Immunol. 5:975-979; Tse and Horner (2008) Semin. Immunopathol. 30:53-62; Tobias & Curtiss (2008) Semin. Immunopathol. 30:23-27; Ropert et al. (2008) Semin. Immunopathol. 30:41-51; Lee et al. (2008) Semin. Immunopathol. 30:3-9; Gao et al. (2008) Semin. Immunopathol. 30:29-40; Vijay-Kumar et al. (2008) Semin. Immunopathol. 30:11-21). As a result of their role in inflammation, it is recognized that down-regulating TLR expression and/or activity may provide a useful means for disease intervention.
To date, investigative strategies aimed at selectively inhibiting TLR activity have involved small molecules (e.g., chloroquine and hydroxychloroquine) (see, for example, WO 2005/007672 and Krieg, A. M. (2002) Annu. Rev. Immunol. 20:709), antibodies (see, for example, Duffy, K. et al. (2007) Cell Immunol. 248:103-114), catalytic RNAi technologies (e.g., small inhibitory RNAs), cyclohexene derivatives (Il et al. (2006) Mol. Pharmcol. 69:1288-1295), lipid derivatives (Akira et al. (2005) Circulation 114:270-274, oligonucleotides containing poly-G sequences (Pawar et al. (2007) J. Am. Soc. Nephrol. 18:1721-1731) and competitive inhibition with methylated or modified oligonucleotides (see, for example, Barrat and Coffman (2008) Immunol. Rev. 223:271-283). Passages of these publications disclosing TLR inhibitors are specifically incorporated by reference.
As a result of their ability to inhibit a TLR-mediated inflammatory response, TLR antagonists are currently being investigated as possible therapeutics for the treatment and/or prevention of certain diseases. However, the role of TLRs in regulating blood cholesterol concentration and/or blood lipid concentration and/or the diseases associated therewith was heretofore unknown.